The ultimate goal of this project is to define the mechanism of herpes simplex virus (HSV) invasion of human cells to establish productive infection. The two serotypes of HSV combined, infect -80 percent of the world adult population. Once infected, a person is infected with these viruses for life. HSV causes a variety of diseases: cold sores, genital lesions resulting from sexually transmitted virus, blindness from ocular infection, severe disseminated disease in newborns, and encephalitis. Disease can resuk from initial infection or re-occurring infection by HSV. Understanding how the virus gains entry into cells to initiate infection can lead to new therapies to block virus infection, prevent disease due to re-occurring infection, or help in the design of vaccines to promote inimunity to HSV infection. In this grant we will further characterize the HveA co-receptor, a human protein that mediates HSV entry into cells, to determine areas of the molecule necessary for virus interactions and promotion of virus entry. We will identify biologically relevant glycosaminoglycans and proteoglycans that enhance virus entry via HveA and characterize their role in the HSV entry pathway. In addition, we will continue the search for other cell products used by HSV to gain entry into cells. The results obtained from these studies will advance our understanding of the cellular components HSV interacts with to gain entry into cells, the cell-virus interactions that promote entry, and methods of enhancing or preventing HSV entry.